Global LEADR pivotal trial results.

BACKGROUND: Implantable cardioverter-defibrillators last longer, and interest in reliable leads with targeted lead placement is growing. The OmniaSecure™ defibrillation lead is a novel small-diameter, catheter-delivered lead designed for targeted placement, based on the established SelectSecure SureScan MRI Model 3830 lumenless pacing lead platform. OBJECTIVE: This trial assessed safety and efficacy of the OmniaSecure defibrillation lead. METHODS: The worldwide LEADR pivotal clinical trial enrolled patients indicated for de novo implantation of a primary or secondary prevention implantable cardioverter-defibrillator/cardiac resynchronization therapy defibrillator, all of whom received the study lead. The primary efficacy end point was successful defibrillation at implantation per protocol. The primary safety end point was freedom from study lead-related major complications at 6 months. The primary efficacy and safety objectives were met if the lower bound of the 2-sided 95% credible interval was >88% and >90%, respectively. RESULTS: In total, 643 patients successfully received the study lead, and 505 patients have completed 12-month follow-up. The lead was placed in the desired right ventricular location in 99.5% of patients. Defibrillation testing at implantation was completed in 119 patients, with success in 97.5%. The Kaplan-Meier estimated freedom from study lead-related major complications was 97.1% at 6 and 12 months. The trial exceeded the primary efficacy and safety objective thresholds. There were zero study lead fractures and electrical performance was stable throughout the mean follow-up of 12.7 ± 4.8 months (mean ± SD). CONCLUSION: The OmniaSecure lead exceeded prespecified primary end point performance goals for safety and efficacy, demonstrating high defibrillation success and a low occurrence of lead-related major complications with zero lead fractures.

Clinical use conditions of lead deployment and simulated lead fracture rate in left bundle branch area pacing.

INTRODUCTION: Left bundle branch area pacing (LBBAP) is achieved by advancing the lead tip deep in the septum. Most LBBAP implants are performed using the Medtronic SelectSecure™ MRI SecureScan™ Model 3830 featuring a unique 4 Fr fixed helix lumenless design. Details of lead use conditions and long-term reliability have not been reported. This study was designed to quantify the mechanical use conditions for the 3830 lead during and after LBBAP implant, and to evaluate reliability using bench testing and simulation. METHODS: Fifty bradycardia patients with implantation of the 3830 lead for LBBAP were enrolled. Use conditions of lead deployment at implantation were collected and computed tomography (CT) scans were performed at 3-month follow-up. Curvature amplitude along the pacing lead was determined with CT images. Fatigue bending was performed using accelerated testing in a more severe environment than routine clinical use conditions. Conductor fracture rate in a simulated patient population was estimated based on clinical use conditions and fatigue test results. RESULTS: The number of attempts to place the 3830 lead for LBBAP was 2.1 ± 1.3 (range: 1-7) with 13 ± 6 lead rotations at the final attempt. Extreme implant conditions were simulated in bench testing with 5 applications of 20 turns followed by up to 400 million bending cycles. Reliability modeling predicted a 10-year fracture rate of 0.02%. CONCLUSIONS: LBBAP implants require more lead rotations than standard pacing implants and result in unique lead bending. Application of simulated LBBAP use conditions to the 3830 lead in an accelerated in-vitro model does not produce excess conductor fractures. IMAGE-LBBP Study ID of ClinicalTrial.GOV: NCT04119323.

Rationale for and use of the lumenless 3830 pacing lead.

Most currently available pacing and defibrillation leads utilize a stylet-based design that facilitates implantation. This has advantages, but also increases the lead diameter and adds the potential for metal fatigued-based conductor failure. A systematic literature search was conducted, and the authors add their twenty-year experience with this lead design. The global experience with lumenless leads was reviewed both for "standard" positioning and with conduction system pacing. Methods for both placement and system modification are reviewed. Lumenless leads have the potential to improve the durability of endocardial pacing and facilitate conduction system pacing.

Interpreting device diagnostics for lead failure.

Implantable cardioverter-defibrillators (ICDs) incorporate automated, lead-monitoring alerts (alerts) and other diagnostics to detect defibrillation lead failure (LF) and minimize its adverse clinical consequences. Partial conductor fractures cause oversensing, but pacing or high-voltage alerts for high impedance detect only complete conductor fracture. In both pacing and high-voltage insulation breaches, low-impedance alerts require complete breach with metal-to-metal contact. Oversensing alerts for pace-sense LF also require complete breach, but not metal-to metal contact. Electrograms (EGMs) from leads with confirmed fractures have characteristics findings. In insulation breach, however, oversensed EGMs reflect characteristics of the source signal. Oversensing alerts that operate on the sensing channel analyze R-R intervals for 2 patterns typical of LF but uncommon in other conditions: a rapidly increasing count of "nonphysiological" short intervals and rapid "nonsustained tachycardias." These alerts are sensitive but nonspecific. Alerts that compare sensing and shock channels define oversensing as sensed events that do not correlate temporally with EGMs on the shock channel. Their performance depends on implementation. Specific advantages and limitations are reviewed. Most ICDs measure impedance using subthreshold pulses. Patterns in impedance trends provide diagnostic information, whether or not an alert is triggered. Gradual increases in impedance do not indicate structural LF, but they may cause failed defibrillation if shock impedance is high enough. Because impedance-threshold alerts are insensitive, normal impedance trends never exclude LF, but an abrupt increase that triggers an alert almost always indicates a header connection issue or LF. Methods for discriminating connection issues from LF are reviewed.

Time course of oversensing and impedance changes in developing implantable cardioverter-defibrillator lead fracture.

Background: Pace-sense conductors comprise a pacing coil to the tip electrode and cable to the ring-electrode. Implantable cardioverter-defibrillator (ICD) lead-monitoring diagnostics include pacing impedance (direct current resistance [DCR]) and measures of oversensing. How they change as fractures progress is unknown. Objectives: To characterize the relationship between oversensing, impedance, and structural changes in ICD leads developing pace-sense conductor fractures. Methods: We performed bending tests on 39 leads connected to ICD generators in an electrolyte bath with simulated electrograms. DCR was recorded every 3 minutes; electrograms were telemetered continuously. Twenty-two leads were tested to develop partial or complete fracture criteria confirmed by imaging, using DCR or DCR variability measured by standard deviation (σDCR). Results are reported for 17 other test leads. Results: Initial oversensing occurred with partial pacing coil fracture vs complete ring cable fracture and correlated with bending-induced DCR peaks. These peaks were too small to be detected by clinical impedance measurements and were characterized by small increases in σDCR (≥0.5 Ω). Impedance threshold alerts occurred at complete pacing coil fracture but only later for ring cable fractures. The oversensing alert triggered before device-detected ventricular fibrillation more frequently than impedance alerts (94% vs 17%; P = .00002). Conclusions: In conductor fracture, early oversensing corresponds to partial pacing coil fracture or complete ring cable fracture and correlates with transient bending-induced impedance increases, which are detected by impedance variability but too small to trigger clinical impedance alerts. This explains why clinical oversensing alerts provide more warning for device-detected ventricular fibrillation than impedance alerts and suggests how to improve impedance diagnostics based on short-term variability.

In vitro modeling accurately predicts cardiac lead fracture at 10 years.

BACKGROUND: Development of a cardiac lead fracture model has the potential to differentiate well-performing lead designs from poor performing ones and could aid in future lead development. OBJECTIVE: The purpose of this study was to demonstrate a predictive model for lead fracture and validate the results generated by the model by comparing them to observed 10-year implantable cardioverter-defibrillator lead fracture-free survival. METHODS: The model presented here uses a combination of in vivo patient data, in vitro conductor fatigue test data, and statistical simulation to predict the fracture-free survival of cardiac leads. The model was validated by comparing the results to human clinical performance data from the Medtronic Sprint Fidelis (Minneapolis, MN) models 6931 (single coil, active fixation) and 6949 (dual coil, active fixation), as well as the Quattro model 6947 (dual coil, active fixation). RESULTS: Median patient age in the single coil Fidelis 6931 population (64 years) was less than in the dual coil Fidelis 6949 and Quattro populations (68 years). Modeled and observed fracture-free survival for Quattro (>97%) was superior to that for Fidelis (<94%). The modeled survival agreed with the observed fracture-free survival data. The average model error was 0.3% (SD 1.2%). CONCLUSION: This model for cardiac lead fracture-free survival using in vivo lead bending measurements and in vitro bench testing can be used to predict lead performance as observed by alignment with field survival data.

In silico assessment of biomedical products: The conundrum of rare but not so rare events in two case studies.

In silico clinical trials, defined as "The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention," have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients' phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern.

Incorporation of stochastic engineering models as prior information in Bayesian medical device trials.

Evaluation of medical devices via clinical trial is often a necessary step in the process of bringing a new product to market. In recent years, device manufacturers are increasingly using stochastic engineering models during the product development process. These models have the capability to simulate virtual patient outcomes. This article presents a novel method based on the power prior for augmenting a clinical trial using virtual patient data. To properly inform clinical evaluation, the virtual patient model must simulate the clinical outcome of interest, incorporating patient variability, as well as the uncertainty in the engineering model and in its input parameters. The number of virtual patients is controlled by a discount function which uses the similarity between modeled and observed data. This method is illustrated by a case study of cardiac lead fracture. Different discount functions are used to cover a wide range of scenarios in which the type I error rates and power vary for the same number of enrolled patients. Incorporation of engineering models as prior knowledge in a Bayesian clinical trial design can provide benefits of decreased sample size and trial length while still controlling type I error rate and power.

Abrasion and fatigue resistance of PDMS containing multiblock polyurethanes after accelerated water exposure at elevated temperature.

Segmented polyurethane multiblock polymers containing polydimethylsiloxane and polyether soft segments form tough and easily processed thermoplastic elastomers (PDMS-urethanes). Two commercially available examples, PurSil 35 (denoted as P35) and Elast-Eon E2A (denoted as E2A), were evaluated for abrasion and fatigue resistance after immersion in 85 °C buffered water for up to 80 weeks. We previously reported that water exposure in these experiments resulted in a molar mass reduction, where the kinetics of the hydrolysis reaction is supported by a straight forward Arrhenius analysis over a range of accelerated temperatures (37-85 °C). We also showed that the ultimate tensile properties of P35 and E2A were significantly compromised when the molar mass was reduced. Here, we show that the reduction in molar mass also correlated with a reduction in both the abrasion and fatigue resistance. The instantaneous wear rate of both P35 and E2A, when exposed to the reciprocating motion of an ethylene tetrafluoroethylene (ETFE) jacketed cable, increased with the inverse of the number averaged molar mass (1/Mn). Both materials showed a change in the wear surface when the number-averaged molar mass was reduced to ≈ 16 kg/mole, where a smooth wear surface transitioned to a 'spalling-like' pattern, leaving the wear surface with ≈ 0.3 mm cracks that propagated beyond the contact surface. The fatigue crack growth rate for P35 and E2A also increased in proportion to 1/Mn, after the molar mass was reduced below a critical value of ≈30 kg/mole. Interestingly, this critical molar mass coincided with that at which the single cycle stress-strain response changed from strain hardening to strain softening. The changes in both abrasion and fatigue resistance, key predictors for long term reliability of cardiac leads, after exposure of this class of PDMS-urethanes to water suggests that these materials are susceptible to mechanical compromise in vivo.